Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme

• Published in: Journal of neurosurgery Vol. 100; no. 2; pp. 320 - 327
• Main Authors: GEIR OLAV HJORTLAND, GARMAN-VIK, Solveig Suzanne, JUELL, Siri, ØYVIND EDON OLSEN, HIRSCHBERG, Henry, FODSTAD, Øystein, ENGEBRAATEN, Olav
• Format: Journal Article
• Language: English
• Published: Park Ridge, IL American Association of Neurological Surgeons 01-02-2004
• Subjects: ADP Ribose Transferases - therapeutic use; Animals; Antibodies, Monoclonal; Antigens, Neoplasm - immunology; Antineoplastic Agents - therapeutic use; Bacterial Toxins - therapeutic use; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - immunology; Cell Line, Tumor; Exotoxins - therapeutic use; Glioblastoma - drug therapy; Glioblastoma - immunology; Humans; Immunotoxins - therapeutic use; Medical sciences; Models, Animal; Neoplasm Transplantation; Neurosurgery; Pseudomonas aeruginosa Exotoxin A; Rats; Rats, Nude; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Survival Analysis; Virulence Factors - therapeutic use; Human; Intracranial; Animal model; Immunotoxin; Nervous system diseases; Rat; Rodentia; Melanoma; Malignant tumor; Glioblastoma multiforme; Survival; Malignant glioma; Toxin; Vertebrata; Mammalia; Treatment; Animal; Surgery; Central nervous system disease; glioma
• ISSN: 0022-3085; 1933-0693
• DOI: 10.3171/jns.2004.100.2.0320

The aim of this study was to target immunotoxin treatment to the high-molecular-weight melanoma-associated antigen (HMW-MAA) and thereby examine any changes in the survival of immunodeficient rats with human glioblastoma multiforme (GBM).
To target treatment specifically to human glioma cells, Pseudomonas exotoxin A (PE) was conjugated to the 9.2.27 antibody, which recognizes the HMW-MAA. Treatment of the antigen-positive glioma cell line U87MG with the resulting 9.2.27-PE caused cytotoxicity with a median inhibitory concentration of 1 ng/ml. Intratumoral 9.2.27-PE treatment of intracranial U87MG tumors in nude rats prolonged the survival of these animals by 43% compared with controls. In additional studies on the use of this targeted treatment, the authors precultured freshly dissected glioblastoma multiforme (GBM) biopsy tissue for 1 to 2 weeks. Inoculation of this tissue into the rat brain resulted in diffuse infiltrative gliomas. The markers glial fibrillary acidic protein and S100 protein were found to be expressed in the original biopsy specimens, as well as in the glioma xenografts in nude rat brains. Intratumoral immunotoxin treatment of such established tumors with 9.2.27-PE was effective and prolonged survival time from 30% to as high as 90% in animals with tumors originating from four different GBM specimens.
Targeted treatment of highly invasive GBMs proved effective, and these results emphasize the clinical relevance of this antigen as a target molecule for immunotoxin treatment of human GBMs.